DESCRIPTION: The applicant proposes to investigate the molecular basis of the human genetic neurodegenerative disease, ataxia telangiectasia (AT). This project will focus on the apparent abnormal response of AT cells to DNA-damaging agents. Dr. Dixon postulates that this abnormal response leads to the enhanced cell death and genetic instability associated with the disease. Abnormal responses of AT cells to ionizing radiation (IR) have been well documented. Dr. Dixon has confirmed that AT cells also respond abnormally to UV radiation in that they fail to exhibit G1/S arrest following exposure to UV. Dr. Dixon proposes to trace the signal transduction events that are known to follow exposure of cells to UV and IR to determine where the defect arises in AT. Two hypothesis will be tested: (1) AT are defective in a critical step in the mitogen-activated signal transduction pathway that is triggered by UV and IR; (2) AT cells are defective in a signal transduction pathway initiated at the level of DNA damage recognition. The specific aims of this project are: (1) to determine whether AT cells exhibit the normal early responses to UV and IR; (2) to determine whether AT cells are defective in DNA damage-induced signal transduction events thought to be related to cell DNA synthesis arrest; (3) to correlate the signal transduction defect with the biological consequences of the AT defect. The ultimate goal of this project is to define the underlying defect in the response of AT cells to UV and IR with the hope that this understanding will lead to the development of strategies for treating this disease.